1. DRUG ABUSE & MENTAL ILLNESS: Progress in Understanding COMORBIDITY DRUG ABUSE & MENTAL ILLNESS: Progress in Understanding COMORBIDITY Donald R. Vereen, Jr., M.D., M.P.H. Special Assistant to the Director National Institute on Drug Abuse Donald R. Vereen, Jr., M.D., M.P.H. Special Assistant to the Director National Institute on Drug Abuse

2. DRUGS BRAIN MECHANISMS ADDICTION ENVIRONMENT HISTORY - previous history - expectation - learning - social interactions - stress - conditioned stimuli - genetics - circadian rhythms - disease states - gender BIOLOGY

3. nucleus accumbens hippocampus striatum frontal cortex substantia nigra/VTA Dopamine Pathways Principal “Pleasure” System of the Brain Dopamine Pathways Principal “Pleasure” System of the Brain 0 50 100 150 200 0 60120180 Time (min) % of Basal DA Output NAc shell Empty BoxFeeding Di Chiara et al. FOOD 100 150 200 DA Concentration (% Baseline) Mounts Intromissions Ejaculations 15 0 5 10 Copulation Frequency Sample Number 12345678 91011121314151617 Scr BasFemale 1 Present Scr Female 2 Present Scr Fiorino and Phillips SEX Natural Rewards Elevate Dopamine Levels 0 0 100 200 300 400 0 0 1 1 2 2 3 3 4 4 5 hr Time After Cocaine % of Basal Release DA Accumbens COCAINE 0 0 100 200 300 400 500 600 700 800 900 1000 1100 0 0 1 1 2 2 3 3 4 4 5 hr Time After Amphetamine % of Basal Release DA Accumbens AMPHETAMINE Source: Di Chiara and Imperato Effects of Drugs on Dopamine Levels

4. Anatomy DA signal Dopamine Cell DA Transporters Brain Dopamine System

5. Cocaine Food DA D2 Receptor Availability Meth Alcohol Dopamine D2 Receptors in Addiction

6. Dominant Subordinate Individually Housed Group Housed * * S.003.01.03.1 0 10 20 30 40 50 Reinforcers (per session) Cocaine (mg/kg/injection) Dominant Subordinate Morgan, D. et al. Nature Neuroscience, 5: 169-174, 2002.

7. And One of the Most Powerful Triggers for Relapse In Recovering Addicts And One of the Most Powerful Triggers for Relapse In Recovering Addicts Research Tells Us That STRESS Can Be A Major Factor In the Initiation of Drug Use… Research Tells Us That STRESS Can Be A Major Factor In the Initiation of Drug Use…

8. Research Has Shown That There Is Overlap Between Neurocircuits That Respond To Drugs and Those That Respond To Stress Research Has Shown That There Is Overlap Between Neurocircuits That Respond To Drugs and Those That Respond To Stress Piazza PV and Le Moal, M, Trends in Pharmacological Science, 19, February 1998; Kreek, MJ and Koob, G, Drug Alcohol Depend, 51, 1998.

9. The Stress Hormone Cycle Hypothalamus Pituitary Gland Pituitary Gland Adrenal Glands Adrenal Glands Kidneys CRF ACTH CORTISOL Stress Responses

10. DRUG USE (Self-Medication) STRESSSTRESS CRFCRF AnxietyAnxiety CRFCRF AnxietyAnxiety What Role Does Stress Play In Initiating Drug Use? What Role Does Stress Play In Initiating Drug Use?

11. Prolonged DRUG USE AbstinenceAbstinence RELAPSERELAPSECRFCRF AnxietyAnxiety What Happens When A Person Stops Taking A Drug? What Happens When A Person Stops Taking A Drug?

12. Addictive Disorder Mental Disorder Addictive Disorders Often Co-Exist With Mental Disorders

13. Addictive Disorders Often Co-Exist with or Predispose to Mental Disorders DSM IV Manual: D evotes ~ 100 pages to describing addiction and dependence disorders DSM IV Manual: D evotes ~ 100 pages to describing addiction and dependence disorders Discusses substance abuse as a confound to diagnosis and Tx Discusses substance abuse as a confound to diagnosis and Tx

14. National Comorbidity Survey (NCS) Nearly half of individuals with a past year substance use disorder also had a mental disorder Mental disorders found to be most prevalent included affective disorders, anxiety disorders, personality disorders, and psychotic disorders Nearly half of individuals with a past year substance use disorder also had a mental disorder Mental disorders found to be most prevalent included affective disorders, anxiety disorders, personality disorders, and psychotic disorders

15. Lifetime Prevalence of Drug Disorders Among Persons With Various Mental Disorders (vs. any Drug Disorder Alone) Lifetime Prevalence of Drug Disorders Among Persons With Various Mental Disorders (vs. any Drug Disorder Alone) Source: Regier,D.A. et al., JAMA 264(19), pp. 2511-2518, November 21, 1990. 0 5 10 15 20 25 30 35 40 45 Schizo- phrenia Schizo- phrenia APD Anxiety Panic Disorder Panic Disorder OCD Bipolar Disorder Bipolar Disorder Depression Any Drug Disorder (alone) Any Drug Disorder (alone)

16. What Do Mental and Addictive Disorders Have in Common? What Do Mental and Addictive Disorders Have in Common? Both are Behavioral Dysfunctions With Similar Neurobiological Basis Both are Behavioral Dysfunctions With Similar Neurobiological Basis

17. Because of this overlap, drugs of abuse can cause symptoms that mimic most forms of mental illness Because of this overlap, drugs of abuse can cause symptoms that mimic most forms of mental illness

18. Cocaine Food DA D2 Receptor Availability Meth Alcohol Dopamine D2 Receptors in Addiction Experimental groups Control groups Cause depression

19. Drug Disorder Cocaine and Methamphetamine Schizophrenia, paranoia, anhedonia, compulsive behavior Schizophrenia, paranoia, anhedonia, compulsive behavior Stimulants Anxiety, panic attacks, mania and sleep disorders Anxiety, panic attacks, mania and sleep disorders LSD, Ecstasy & psychedelics Delusions and hallucinations Alcohol, sedatives, sleepaids & narcotics Alcohol, sedatives, sleepaids & narcotics Depression and mood disturbances Depression and mood disturbances PCP & Ketamine Antisocial behavior

21. Some drugs of abuse have a mechanism of action similar to that of drugs used as psychotherapeutic agents Some drugs of abuse have a mechanism of action similar to that of drugs used as psychotherapeutic agents Significance: rationale for self-administration Significance: rationale for self-administration

22. serotonin synaptic terminal Synaptic vesicle Postsynaptic target Activate transmitter receptors Causes an effect transporter Prozac & Cocaine block

23. Chronic use of some of these drugs may alter the way the brain functions, making persons particularly susceptible to mental illness Chronic use of some of these drugs may alter the way the brain functions, making persons particularly susceptible to mental illness

26. Double People With Comorbid Mental and Addictive Disorders Have a Brain Disease People With Comorbid Mental and Addictive Disorders Have a Brain Disease Double Mental Disorder Mental Disorder Addictive Disorder Addictive Disorder Comorbid Disorders Comorbid Disorders

27. Drug Abuse Increasing Knowledge About Any One of These Commonly Co-existing Problems May Help Us Better Understand the Others Increasing Knowledge About Any One of These Commonly Co-existing Problems May Help Us Better Understand the Others Depression HIV/AIDS Risky Sexual Behavior Risky Sexual Behavior

28. Email from a Drug Addicted Subject 11.05.2003 “ I am a Dutch 30 year old male very addicted to marihuana, alcohol and crack cocaine. I have no social life and no job and feel more and more isolated and have less and less hope to brake free of this hell. …. My life is a mess and did several attempts to brake with my addictions in the past. … Now as I am so tired of trying I find it very difficult to keep on fighting, even more so, because of the depressed moods and feeling of dissatisfaction while being clean. I do not feel whole without the damned drugs any way ”